1. Field of the Invention
This invention relates to long acting analgesics Nalbuphine polyester derivative and to pharmaceutical compositions comprising those compounds.
2. Description of the Related Art
New type of opiods drugs such as Buprenorphine, Nalbuphine, Butorphanol, so-called narcotic agonist-antagonist analgesics have been developed. They exhibit a dual action of agonist and antagonist on opiods-receptors as reported by Schmidt, W. K. et al (Drug Alcohol Depend. 14, 339, 1985), where pointed out that dual action of those drugs not only had high affinity to opium receptor but also served as anatagonist. For example, Nalbuphine was the antagonist for Mu receptor and agonist for Kappa receptor. Those agonist/antagonist drugs have improvement on untoward effects of opiods drugs, such as addiction and respiratory suppression.
Shafer, S. L. et al. have investigated the analgesic potency of narcotic agonist-antagonist analgesics. They have found that when compared with the more opiods drugs to elicit the same analgesic effect, the dose needed for Morphine and Nalbuphine are 10 mg; for Buprenorphine is 0.3 mg; for Butorphanol is 2 mg (Anesthesiology, 74, 53, 1991). According to the publication by Schmidt, W. K. et al, supra (1985), Nalbuphine is the most widely used one and has excellent therapeutic efficacy. After continuous use of Nalbuphine for 6 months, no significant addiction and addition was found. Those narcotic agonist-antagonist analgesics exhibits only slight respiratory inhibition. In clinical use, Nalbuphine is safer than the traditional narcotic analgesics.
An ideal analgesic should exhibit short onset time, should be long acting, potent, should cause no addiction, no inhibition of the cardiac or cardiovascular system, no respiratory inhibition, and should have few other adverse effects which were suggested by Bovill, J. G. et al. (Drugs, 33, 520, 1987). For the relief of pain, local anesthetics like Xylocaine or Bupivacaine can only be applied to restricted areas. In addition, local anesthetics are short acting and even when they are given intracerebroventricularly, the duration of action hardly exceeds 6 hours. Therefore, for the severe and acute pain caused by cardiac, pulmonary, abdominal, osteopathia, and obstetrical surgery, severe burn injury and terminal stage of cancer, local anesthetics are not satisfactory.
Non-narcotic analgesics, such as Acetaminophen and aspirin can relieve pain of only low intensity, such as pain due to headache or toothache but they do not help in the case of serious pain. Bovill, J. G. et al. reported in Drugs volume 33, page 520 regarding that a strong narcotic analgesic drug should have action on Mu receptor in central nervous system. Hayes, A. G. et al. (Br. J. Pharmacol. Vol 79, 731, 1983) have reported that all the narcotic analgesics exhibit the same disadvantages with respect to addiction, and addition and respiratory inhibition. In addition, the duration of action of the narcotic analgesics is somewhat short. Normally, to maintain the analgesic effect, the dosing interval needs to be set at 3-5 hours. Even when the agent is administered to the spinal marrow, the duration of action could not be longer than 48 hours.
According to Schmidt, W. K. et al. suggested and clinical cases found that Nalbuphine was widely used in those narcotic agonist-antagonist analgesics. Nalbuphine has been found to be effective in controlling severe and deep pain caused by cardiac, pulmonary, abdominal, osteopathia, and obstetrical surgery, severe burn injury and the terminal stages of cancer via various parenteral administration routes, such as intramuscular, intravenous, intrathecal and intracerebroventricularly. However, the duration of analgesic action was short. According to Wang, J. J. et al. revealed data in 1985 Ma Tsui Hsueh Tsa Chi, volume 23, page 3, regarding the duration for different administration routes for Nalbuphine. For intravenous parenteral administration, the analgesic effect was maintained 3 to 5 hours, for intracerebro-ventricularly it was maintained 6 to 8 hours. For dramatic pain that needed hospitalization, multiple regiments were needed, and the medication cost was highly increased.
A Nalbuphine analogue compound was found in U.S. Pat. No. 4,673,679 which discloses the 3-morphine derivatives, in which the substitution group R was methyl, propyl, methyl propyl, methyl cyclopropyl, cyclopentyl; R.sub.1 and R.sub.2 were hydrogen and carboxyl groups respectively, R.sub.2 could also be lactone or methylene groups; R.sub.3 and R.sub.4 were hydrogens or bonded to oxygen; R.sub.5 was an alkanoyl group containing 2 to 18 carbons, or benzoyl, halides. They also disclose pharmaceutical dosage forms for sublingual, buccal, or nasal administration.
WO patent No. 82/03,768 revealed that narcotic antagonists, narcotic analgesics and related compounds such as Nalbuphine were prepared with a pH adjusting agent, jelling agent, emulsifier, emollient, cellulose derivatives, Tween 80, etc. and dosage forms such as nasal solution, nasal suspension, nasal ointment, and nasal jelly, containing those compounds which are adapted for nasal administration. European patent A1 No. 0,170,090 revealed the substituted benzolate ester prodrug derivative of 3-hydroxy-morphinans. Those compounds are useful as analgesics or narcotic antagonists, and provide dosage forms for capsules, tablets, suspensions, suppositories, and injections. U.S. Pat. No. 4,722,928 revealed N-oxide prodrug derivative of 3-hydroxy-morphine and partial morphinan analgesics, agonist-antagonists, and narcotic antagonists are useful therapeutic effects. Those compounds where prepared in various dosage forms with diluents, carriers such as magnesium stearate, cellulose derivatives, lactose, starch for tablets, powder, capsules, suspensions, syrups etc. for orally administration dosage forms. In view of the forgoing, it is apparent that all of these patents which contained Nalbuphine but didn't include Nalbuphine polyester derivative.